Zhihuang Hu

Patients with Exon 19 Deletion Were Associated with Longer Progression-Free Survival Compared to Those with L858R Mutation after First-Line EGFR-TKIs for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Backgrounds It has been extensively proved that the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is superior to that of cytotoxic chemotherapy in advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, the question of whether the efficacy of EGFR-TKIs differs between exon 19 deletion and exon 21 L858R mutation has not been yet statistically answered. Methods Subgroup data on hazard ratio (HR) for progression-free survival (PFS) of correlative studies were extracted and synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect and direct methods, respectively. Results A total of 13 studies of advanced NSCLC patients with either 19 or 21 exon alteration receiving first-line EGFR-TKIs were included. Based on the data from six clinical trials for indirect meta-analysis, the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20–0.38, P<0.001) in patients with 19 exon deletion and 0.47 (95% CI 0.35–0.64, P<0.001) in those with exon 21 L858R mutation. Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation  = 0.59, 95% CI 0.38–0.92; P = 0.019). Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation  = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies. Conclusions For advanced NSCLC patients, exon 19 deletion might be associated with longer PFS compared to L858 mutation at exon 21 after first-line EGFR-TKIs.

Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations.

Background Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons. Methods We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments. Results Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib. Conclusions The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.

National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China

INTRODUCTION Treatment choice for NSCLC in China has not previously been reported. This paper explores the clinical practice and adherence to treatment guidelines for NSCLC. METHODS A specifically designed questionnaire was used. It consisted of personal information of the responders and treatment details (patient identification data was excluded). Questionnaires were delivered to doctors in 12 major cities in China. Doctors were asked to answer the questionnaires based on real cases in their daily practice. RESULTS 987 cases of NSCLC were included. In first-line chemotherapy, regimens were mostly platinum-based among which gemcitabine plus platinum was predominately used (27.4%), followed by docetaxel plus platinum (16.2%) and paclitaxel plus platinum (13.5%). In second-line therapy some were treated with single agents, such as docetaxel (12.9%), gefitinib (11.1%), pemetrexed (9.3%), and erlotinib (3.5%). 44.5% were with doublet therapy. Detection rate of epidermal growth factor receptor (EGFR) mutation was only 9.6% because of the limited prevalence of testing technology. EGFR mutation rate was 46.8%. EGFR-tyrosine kinase inhibitors (TKIs) were used more frequently as salvage (14.8%) rather than upfront therapy (5.3%). CONCLUSIONS This survey reveals the daily clinical treatment for NSCLC in China. Overall data showed modest adherence to the national guideline (NCCN guideline Chinese version) for first-line chemotherapy. We believe this survey is valuable to provide a reference for further clinical trial design and policy making.

Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma

BACKGROUND Previous results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term efficacy and late toxic effects. PATIENTS AND METHODS Between January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m(2) weekly for six cycles (n = 59). RESULTS After a median follow-up of 114 months (range 18-139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups. CONCLUSION(S) The long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect.

Ratio of C-Reactive Protein/Albumin is An Inflammatory Prognostic Score for Predicting Overall Survival of Patients with Small-cell Lung Cancer

Recent studies have indicated that the C-reactive protein/ albumin (CRP/Alb) ratio is associated with clinical outcomes in patients with hepatocellular carcinoma (HCC). We examined the prognostic value of this ratio in patients with small-cell lung cancer (SCLC). In this retrospective study, a total of 367 eligible SCLC patients were analyzed and the correlation between the pretreatment CRP/Alb ratio and overall survival (OS) was investigated. The optimal cutoff level of CRP/Alb ratio was at 0.441. A low and high CRP/Alb ratio was assigned to 65.1% and 34.9% of patients, respectively. The median OS of patients with a high CRP/Alb ratio was worse than those in the low group (13.70 vs 18.90 months HR, 1.34; p = 0.005). Disease stage (p < 0.001), performance status (PS) (p < 0.001) and pretreatment LDH (p < 0.001) were also significant predictors of OS. Multivariate analyses showed that the CRP/Alb ratio is an independent prognostic factor (p = 0.025). This study demonstrated that the CRP/Alb ratio could independently predict OS in patients with SCLC, and had comparable prognostic value to other known prognostic markers. Therefore, the CRP/Alb ratio could have prognostic value and be a measurable biomarker in patients with SCLC.

Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma

BACKGROUND We aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS It was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m(2) i.v. day 1, and 5-FU 1000 mg/m(2)/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib. RESULTS In total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8-8.4 months), and the median overall survival was 11.8 months (95% CI 10.6-18.7 months). Major toxic effects included hand-foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases. CONCLUSION Combination of sorafenib, cisplatin (80 mg/m(2)) and 5-FU (3000 mg/m(2)) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for Chinese patients with squamous cell carcinoma of lung harboring EGFR mutation

OBJECTIVE Epidermal growth factor receptor (EGFR) mutation mostly occurred in lung adenocarcinoma, rarely in squamous cell carcinoma (SQCC). EGFR mutation rate in SQCC varied in previous reports, and the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in SQCC harboring EGFR mutation has not yet been fully evaluated. The aim of this study was to investigate the efficacy EGFR-TKIs for Chinese patients with SQCC of lung harboring EGFR mutation. PATIENTS AND METHODS Two cohorts of patients were analyzed. The first cohort included 146 consecutive post-operation SQCC patients from January 2008 to October 2012. The second cohort included 63 patients with advanced SQCC receiving EGFR-TKIs treatment. EGFR mutation analysis was performed with Real-time PCR method. The pathologic diagnosis was validated with immunohistochemistry (IHC) for patients harboring activated EGFR mutation. And the efficacy of EGFR-TKIs in squamous cell carcinoma of lung (SQCC) was evaluated in patients with activated EGFR mutations. RESULTS In the first cohort, 146 resected patients, EGFR mutations were detected in 3 patients, with the mutation rate of 2.0%. In cohort two, 63 patients treated with EGFR-TKIs, 15 patients possessed activated EGFR mutations. The response rate and disease control rate in these patients was 26.7% and 66.7% respectively. 5 patients had disease control over 6 months. The progression free survival (PFS) in EGFR-mutated patients was 3.9 months. CONCLUSIONS In Chinese SQCC patients, EGFR mutation rate was extremely low. EGFR-TKIs seemed to be less effective in EGFR-mutated SQCC patients, but some patients could still obtain benefit from EGFR-TKIs. To identify this part of patients, further study was warranted in the future.

PD-L1 is remarkably over-expressed in EBV-associated pulmonary lymphoepithelioma-like carcinoma and related to poor disease-free survival

Backgroud Programmed cell death-ligand 1 (PD-L1) and driver mutations are commonly seen in non-small-cell lung cancer (NSCLC). However, the prevelance of PD-L1 over-expression and its prognostic value in Epstein–Barr virus (EBV) associated pulmonary lymphoepithelioma-like carcinoma (LELC) remains poorly understood. Methods A total of 214 NSCLC patients and 113 surgically treated pulmonary LELC patients were included. Paraffin-embedded tumor sections were stained with PD-L1 antibody. Correlations between PD-L1 expression and clinicopathological features as well as survival outcomes were analyzed. Results The frequency of PD-L1 over-expression in NSCLC was 51.4%. No significant association was observed between common driver mutations and PD-L1 over-expression. Remakably, the positive rate of PD-L1 in pulmonary LELC was 74.3%. High PD-L1 expression was associated with impaired diseas-free survival (DFS) compared with low PD-L1 expression (p = 0.008). Multivariate analysis shows that PD-L1 expression level, N stage and M stage were independent prognostic factors for DFS. N stage and M stage but not PD-L1 expression level were significantly associated with overall survival (OS). Conclusions PD-L1 over-expression was not related to common driver mutations in NSCLC. Pulmonary LELC have remarkably high incidence of PD-L1 expression. PD-L1 was a negative prognostic factor for DFS in surgically resected pulmonary LELC. These findings may provide a rationale for immunotarget therapy in this virus-associated lung cancer.

Personalized Estimate of Chemotherapy-Induced Nausea and Vomiting: Development and External Validation of a Nomogram in Cancer Patients Receiving Highly/Moderately Emetogenic Chemotherapy.

AbstractChemotherapy-induced nausea and vomiting (CINV) is presented in over 30% of cancer patients receiving highly/moderately emetogenic chemotherapy (HEC/MEC). The currently recommended antiemetic therapy is merely based on the emetogenic level of chemotherapy, regardless of patients individual risk factors. It is, therefore, critical to develop an approach for personalized management of CINV in the era of precision medicine.A number of variables were involved in the development of CINV. In the present study, we pooled the data from 2 multi-institutional investigations of CINV due to HEC/MEC treatment in Asian countries. Demographic and clinical variables of 881 patients were prospectively collected as defined previously, and 862 of them had full documentation of variables of interest. The data of 548 patients from Chinese institutions were used to identify variables associated with CINV using multivariate logistic regression model, and then construct a personalized prediction model of nomogram; while the remaining 314 patients out of China (Singapore, South Korea, and Taiwan) entered the external validation set. C-index was used to measure the discrimination ability of the model.The predictors in the final model included sex, age, alcohol consumption, history of vomiting pregnancy, history of motion sickness, body surface area, emetogenicity of chemotherapy, and antiemetic regimens. The C-index was 0.67 (95% CI, 0.62–0.72) for the training set and 0.65 (95% CI, 0.58–0.72) for the validation set. The C-index was higher than that of any single predictor, including the emetogenic level of chemotherapy according to current antiemetic guidelines. Calibration curves showed good agreement between prediction and actual occurrence of CINV.This easy-to-use prediction model was based on chemotherapeutic regimens as well as patients individual risk factors. The prediction accuracy of CINV occurrence in this nomogram was well validated by an independent data set. It could facilitate the assessment of individual risk, and thus improve the personalized management of CINV.

The Efficacy of Combining Antiangiogenic Agents with Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer Who Failed First-Line Chemotherapy: A Systematic Review and Meta-Analysis

Background The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients. Methods We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients. Results Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02). Conclusions This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy.